This invention relates to a method for preparing halogenated compounds, and more specifically, for labeling organic compounds with radioactive halogen.
Radioactive isotopes of halogen atoms, especially iodine, have proven to be very useful for labeling both large and small organic molecules. Radioactively labeled compounds have great utility by virtue of the ease with which extremely small amounts of them they may be detected and measured. Radioiodinated compounds are especially useful because the gamma rays which the iodine isotopes emit are detectable directly without the use of a costly and cumbersome scintillation system and because the isotopes have relatively short half-lives.
Radioiodinated compounds have two primary uses. The first, radioimmunoassay, involves the use of antibodies raised against a specific molecule, called an antigen, for its detection in minute amounts. The second major use of radioiodinated compounds is in nuclear medical imaging. Compounds that localize in a particular organ or tissue are used to carry a radiolabel whose emissions are detected outside the body.
An example of a recently developed nuclear medical imaging agents is the compound [.sup.125 I]IBZM, (S)-3-[.sup.125 I]-iodo-2-hydroxy -6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)]methylbenzamide, which has been found to bind specifically to the dopamine D-2 receptor with stereospecificity. Kung, H.F., et al., "Comparison of In Vivo D-2 Dopamine Receptor Binding of IBZM and NMSP in Rat Brain," Nucl, Med. Biol., Vol. 15, No. 2, pp. 203-208, 1988. A related imaging agent is the compound [.sup.125 I]IBZP, (R)-(+)-8-[.sup.125 I]-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenol-1-H-3-benzazepine-7ol. Kung, H.F. et al., Op. cit., pp 187-193. The agent IBZP is specific for Dopamine D-1 receptor. Since .sup.125 I-isotopes are generally not useful for labelling imaging agents, by virtue of their relatively long half-lives (60 days) and low gamma-emission (30-65 Kev), it is proposed that .sup.123 I-labelled BZM or BZP (.sup.l23 I has a half life of 13 hours, gamma energy l59ke V) would be useful as an imaging agent for the investigation of dopamine D-1 and D-2 receptors in humans, and, thus, as a tool for studying the biochemistry and metabolism of the living human brain.
For .sup.123 I-labelled agents to be practically useful, there must be a method for quickly, conveniently and efficiently labelling the agents with the radioactive isotope. The short half-life of the isotope is beneficial from the standpoint of safety to the patient to whom it will be administered but also dictates that the labelling procedure be one which can be quickly accomplished. The labelling procedure should also be one which will lead to a labeled molecule of high specific activity. Specific activity is a measure of the radioactivity of a labeled molecule, maximum specific activity being obtained when each molecule in the preparation is radiolabeled.
Methods for labelling organic molecules with radioactive iodine have been reviewed by Seevers and Counsell, "Radioiodination Techniques for Small Organic Molecules," Chem. Rev., 1982, 82, 575-590. As discussed therein, the earliest methods of radiolabeling involved application of methods known in the art for iodinating phenols with stable iodine. Radioactive molecular iodine was the most commonly employed labeling reagent; however, since radioactive iodine is usually available as sodium iodide, a means of oxidation had to be employed to obtain radioactive molecular iodine. Agents such as ammonium persulfate, hydrogen peroxide, ferric sulfate or an iodide/iodate system were used for oxidation prior to radiolabeling. There are, however, a number of disadvantages to the use cf molecular iodine for radiolabeling. First, since half of the label ends up as radioiodide, the maximum possible radiochemical yield is only 50%. Second, the prior oxidation step involves some loss of radioactivity and increased radiation exposure to the operator. Third, the volatility of molecular iodine greatly magnifies the hazards of the labeling procedure.
Although not related to labeling with radioactive isotopes, it should be noted that the nonradioactive iodination of benzene and phenyl compounds with a mixture of peroxyacetic acid and molecular iodine have been reported in excellent chemical yield. Ogata, Y. and Nakajima, K., "Iodination of Aromatic Compounds with a Mixture of Peroxyacetic Acid and Iodine," Tetrahedron, 20, 43 (1964), and "Studies on the Iodination of Aromatic Compounds by a Mixture of Peroxyacetic Acid and Iodine," Tetrahedron, 20, 2751 (1964). To the knowledge of the inventor, no reference has suggested the use of peracetic acid oxidizing agent when the source of iodine was iodide ion rather than molecular iodine.
To avoid the disadvantages associated with iodination methods using molecular iodine, techniques using radioactive iodide were developed. The most widely used technique uses chloramine T as an oxidizing agent. The active iodinating moiety is generated by oxidizing I.sup.- to I.sup.+, by which the electrophilic oxidative iodination of phenols and other activated aromatic rings systems take place. Meyers, J., et al., J. Nucl. Med., 16, 835 (1975); Baldwin, R.M., et al., J. Radioanal. Chem., 65, 163 (1981). The chloramine T technique, however, also suffers certain disadvantages. One problem is that the compound to be labeled is exposed to harsh oxidizing conditions which can lead to undesirable side reactions. Another problem is that radiolabeling reactions involving chloramine-T usually require a fine control of the molar ratio of oxidant and substrate and of the reaction time. Finally, the chloramine-T reaction often produces radioactive and non-radioactive side products which must be separated from the desired iodinated compounds. A number of other oxidants for radioactive iodination have been reported, and these include hydrogen peroxide (H, -J. Machulla, M. Marsman and K. Dutschka, J. Radioanal. Chem., 56, 253 (1980); ammonium persulfate (R.C. Gilmore, Jr., M.C. Robbins and A.F. Reid, Nucleonics, 12(2), 65 (1954); nitric acid (W.G. Keough and K.G. Hofer, J. Labeled Comod. Radiopharm., 14, 83 (1977); iodate (P.K. Chang and A.D. Welch, J. Med. Chem., 6, 428 (1963); and chlorine water (G. Ehrensvard, J. Liwekvist, K. Mosbach and P. Fritzson, Acta. Chem. Scand., 12, 485 (1958). However, there remains a need for a method for quickly, conveniently and efficiently labelling organic molecules with radioactive halogens such as .sup.123 I.